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Updated: Feb 11, 2026

Assessment of Morphine-induced Hyperalgesia and Analgesic Tolerance in Mice Using Thermal and Mechanical Nociceptive Modalities
07:23

Assessment of Morphine-induced Hyperalgesia and Analgesic Tolerance in Mice Using Thermal and Mechanical Nociceptive Modalities

Published on: July 29, 2014

34.1K

Complex formation between the vasopressin 1b receptor, β-arrestin-2, and the μ-opioid receptor underlies morphine

Taka-Aki Koshimizu1, Kenji Honda2, Sachi Nagaoka-Uozumi2

  • 1Department of Pharmacology, Division of Molecular Pharmacology, Jichi Medical University, Shimotsuke, Tochigi, Japan. t_koshi@jichi.ac.jp.

Nature Neuroscience
|May 2, 2018
PubMed

Insights

Blocking vasopressin 1b receptors (V1bRs) delays morphine tolerance by preventing receptor complex formation. This approach enhances morphine analgesia without increasing tolerance, offering a new therapeutic strategy.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Molecular Biology

Background:

  • Chronic morphine use leads to opioid tolerance, reducing pain relief.
  • The mechanisms by which nonopioid neurotransmitters influence opioid tolerance are not fully understood.

Purpose of the Study:

  • To investigate the role of vasopressin 1b receptors (V1bRs) in the development of morphine tolerance.
  • To elucidate the molecular mechanisms underlying V1bR involvement in opioid tolerance.

Main Methods:

  • Utilized knockout mice lacking V1bRs and pharmacological antagonism of V1bRs in the rostral ventromedial medulla.
  • Examined V1bR and μ-opioid receptor (MOR) co-localization and interactions using cell-based assays.
  • Investigated the role of β-arrestin-2 and ERK phosphorylation in vasopressin-mediated signaling.

Main Results:

  • Morphine tolerance was delayed in V1bR-deficient mice and upon V1bR antagonist administration.
  • Vasopressin enhanced morphine-binding affinity to cells co-expressing V1bR and MOR.
  • V1bR, β-arrestin-2, and MOR complex formation mediated vasopressin-induced ERK phosphorylation and adenylate cyclase sensitization.
  • A specific leucine-rich segment in V1bR was crucial for β-arrestin-2 association.

Conclusions:

  • Inhibition of μ-opioid-receptor-associated V1bR is a viable strategy to enhance morphine analgesia.
  • Targeting V1bR signaling can mitigate the development of analgesic tolerance.
  • This research offers a novel therapeutic avenue for improving opioid pain management.

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